Evidence for homeopathic principles in the basic sciences Paolo Bellavite Department of Medicine, University of Verona (I) Email:
[email protected]
Cape Town 5 Sept 2018
© P. Bellavite, Università di Verona
Evidence for homeopathic principles in the basic sciences 1. 2. 3. 4.
Introduction Similia Microdose and «potency» Key points
Note: Tables and figures of this presentation are available at: http://www.paolobellavite.it/news.html Cape Town 5 Sept 2018
© P. Bellavite, Università di Verona
“Art” and “Science” in Medicine
As every field of medicine, homeopathy is characterized by aspects which belong to the “art” of healing and by aspects which are belonging to scientific medicine. The two “wings” are not in contrast and should be taken into account for a whole evaluation of the medical system. A rigorous scientific research has been carried out in the last 30 years and now we have over 6000 scientific papers in top literature (Pubmed)
Cape Town 5 Sept 2018
© P. Bellavite, Università di Verona
SCIENTIFIC INVESTIGATION OF THE HOMEOPATHIC PRINCIPLES HOW DOES IT WORK?
•In vivo (animal models) •In vitro (cellular systems) •Physico-chemistry (“water memory”) •Dynamic systems theory
Basic sciences
•Drug composition •Drug targets (cells/organs/systems)
SIMILIA MICRODOSE AND PRINCIPLE “POTENCY”
TOTALITY OF CURE DOES IT WORK? •Adverse effects? •Is it cost-effective? •COULD IT WORK BETTER? Cape Town 5 Sept 2018
Clinical research
• • • •
Provings Observational studies Prognostic factors research Randomized trials © P. Bellavite, Università di Verona
Laboratory models and homeopathy •
Homeopathy is directed toward the complexity of the whole organism, through mechanisms that are not yet clarified.
•
Such action may also appear at the cell level
•
Given the holographic fractal nature of all complex systems, the fundamental rules of biological responses/pathologies can be unraveled at any level of nature, from the complex organism to the single cells (eg. complete genome in each cell)
•
Our working hypothesis (and dr. Benveniste was a pioneer!) is that the biological investigation at the cell level, makes it possible to look at homeopathy in a new and fully rational light
Complex systems
Objects of research:
Drug targets (receptors, enzymes, gene expression) Specific mechanisms of action Cape Town 5 Sept 2018
© P. Bellavite, Università di Verona
Basic research in homeopathy TYPICAL CELLULAR MODELS https://www.ncbi.nlm.nih.gov/pubmed/26678723
• Lymphocytes (Colas, Bildet, Bastide, Wagner, Chirila, Fimiani, Seligmann, Toliopulos, Coelho Moreira, Guimarães, Burbano)
• Basophils (Poitevin, Sainte Laudy, Belon, Davenas, Ovelgonne, Hirst, Mannaioni, Ennis, Bellavite, Baumgartner)
• Granulocytes, macrophages (Poitevin, Fletcher, Bellavite) • Cell lines: Fibroblasts (Boiron, Mansvelt, Fougeray, Valentiner, Saini) Renal cells (Delbancut), Hepatoma (van Wijk, Wiegant), Prostate epitelial (Bigagli) . Neurocytes (Jonas, Bellavite), Macrophages (Bonamin, De Oliveira, Olioso, Marzotto, Siqueira)
• Vegetable cells (Guillemain, Bornoroni, Betti, Sukul, Baumgartner) • Cancer cells (Jonas, Frenkel, Khuda-Buckhsh, Arora, Saha, Das)
Cape Town 5 Sept 2018
© P. Bellavite, Università di Verona
Results of models of basic research submitted to replication (total = 98 studies until 2015)
Opposite result
No effect
Positive replication
External replications Multicentre Internal replications
Initial studies-20
0
20
40
https://www.ncbi.nlm.nih.gov/pubmed/26678723
Replications of fundamental research models in ultra high dilutions 1994 and 2015 e update on a bibliometric study. Peter Christian Endler, Paolo Bellavite, Leoni Bonamin, Tim Jager and Sintia Mazon Homeopathy (2015) 104, 234e245
Cape Town 5 Sept 2018
© P. Bellavite, Università di Verona
Some (not all!) players
Jacques Benveniste – F (Basic research)
Madeleine Bastide - F (Immunology)
Vittorio Elia - I (Chemistry)
Lucietta Betti - I (Botanical research)
Carla Holandino - BR (Pharmacology)
Philippe Belon - F (Basic research)
Louis Rey - F (Thermoluminescence)
Christian Endler - A Leoni Bonamin – BR (Basic research) (Basic research)
A. Khuda Bukhsh - Ind (Biochemistry)
Cape Town 5 Sept 2018
Nirmal Sukul - Ind (Basic science)
Thank you Peter! © P. Bellavite, Università di Verona
Evidence for homeopathic principles in the basic sciences 1. 2. 3. 4.
Introduction Similia Microdose and «potency» Key points
Note: Tables and figures of this presentation are available at: http://www.paolobellavite.it/news.html Cape Town 5 Sept 2018
© P. Bellavite, Università di Verona
TESTING HOMEOPATHY MAIN HYPOTHESIS IS A SCIENTIFIC ISSUE
“The majority of substances have more than one action; the first is a direct action, which gradually changes into the second, which I call its indirect secondary action. The second is generally the opposite of the first” C.F.S. Hahnemann, 1796 TRUE
C.F.S. Hahnemann
FALSE
SCIENTIFIC RESEARCH + Cape Town 5 Sept 2018
© P. Bellavite, Università di Verona
Janus Ancient symbol of similitude
ENTRY
EXIT
PAST
FUTURE
BEGINNING
ENDING
NEGATIVE
POSITIVE Axis (Roman coin)
Cape Town 5 Sept 2018
© P. Bellavite, Università di Verona
SCIENTIFIC REEVALUATION OF THE HOMEOPATHIC “SIMILE”
GENERAL HYPOTHESIS:
The “therapeutic similarity” in drug action may be fundamentally based on the widespread phenomenon of inversion of biological effects dependent on the following factors:
1. the dose of the drug, and/or 2. the pathophysiological state of the target
Main references in: Bellavite et al .: ECAM Journal 2007 (available online https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1876612/pdf/nel117.pdf) Cape Town 5 Sept 2018
© P. Bellavite, Università di Verona
Experimental studies on APIS M. (1975-2015) Madeleine Bastide (1935-2007) 1975 Homeopahtic dilutions (7C-9C) of bee venom (Apis mellifica and Apium
1988 1993
2004 2014
virus, have a protective and curative effect on X-ray induced erythema in albino guinea pig (Bastide1975, Bildet1989, 1990) High dilutions of Apis mellifica inhibit basophil degranulation (histamine release) (Poitevin et al., 1988) Our group studied the effects of homeopathic preparations of Apis mellifica (and Histamin) on rat paw edema induced by the injection of inflammatory doses of histamine. High dilutions of up to 30D had a small but significant inhibitory effect on the development of edema (Conforti et al.,1993). We described a small inhibiting effect of Apis mellifica (4 D, oral drops) in the carrageenan-induced edema in rats . Bigagli and coworkers (2014) showed with microarray techniques that Apis mellifica TM modifies expression of hundreds of genes in human prostate epithelial cells; dynamized dilutions (3C, 5C and 7C) still exert significant effects on genes involved in inflammation and oxidative stress
Cape Town 5 Sept 2018
© P. Bellavite, Università di Verona
FIRST «homeopathic» paper in top Journal
Bernard Poitevin
Cape Town 5 Sept 2018
© P. Bellavite, Università di Verona
EXAMPLES OF INVERSE EFFECTS IN LABORATORY SYSTEMS (“conventional” dilutions)
System
Agent
First effect
Inverse effect
Ref.
Yeast
Heavy Metals
Block growth
Low doses increase growth
Schulz 1988 Martius 1923 Stebbing 1982
Fibroblasts Wheat
Arsenite Cadmium
Cell toxicity
Low doses protect from toxicity or stimulate DNA synthesis
vanWijk 1995 vanWijk 1997 V.Zglinicki 1992 Betti 1997-2000
Neurons
Naloxone
Antagonizes morphine
Low doses enhance the effect of morphine
Crain 1995
Neurons
b-amyloid
Toxic for mature cells
Promotes growth of young cells
Yankner 1990 See also Puzzo 2018
Epithelial cells Tumor cells
Oxidants
Short-term/high doses decrease viability
Long-term/low doses increase viability
Da Silva 1996 Jenkins 1995
Macrophages
Interfererons Endotoxins
Activation of resting cells
Inhibition of pre-activated cells
Adams 1992
Platelets
Diclofenac
Inhibit functions
Stimulate platelet adhesion
Andrioli-Bellavite 1997
Leukocytes
Bacterial peptides
Stimulate adherence
Low doses inhibit adherence
Bellavite 19931997
http://www.paolobellavite.it/files/246_2011SeminarioRomaRey_58wwpoeh.pdf Cape Town 5 Sept 2018
© P. Bellavite, Università di Verona
Inverse effects of Amyloid-b according to the dose https://www.ncbi.nlm.nih.gov/pubmed/19118188
Cape Town 5 Sept 2018
© P. Bellavite, Università di Verona
THE “SIMILE” IN THE LIFE: EXAMPLES OF “OPPOSITE” or “INVERSE” EFFECTS (Homeopathic dilutions) Ref: https://www.ncbi.nlm.nih.gov/pubmed/17549232
System
Agent
“Conventional” effect
“Homeopathic” effect
Ref.
Rat, Guinea pig
Histamine Pro-inflammatory Histamine (30x), Lung histamine Bastide 1975,Poitevin Lung Histamine agent (18c) and Apis mellifica (7c/10c) 1988, Bildet 1990 Apis mell. reduce inflammation symptoms Conforti 1993
Rat, Mouse
Arsenic
Whole body and liver toxicity
Ars. high dilutions (7c-30c) protect from intoxication
Lapp 1955; Wurmser 1955; Cazin1987-1991; Banerjee,P, Khuda-Bukhsh 1998-2000
Rat
Nux vomica
Neurohinibition (strychnine)
Reduces alchool-indced sleeping time
Sukul et al., 1999
Rat
Acetylsalycilic acid
Antithrombotic
Acetylsalycilic acid (5c-15c) has Beulogne-Malfatti,Doutremepuich , Eizayag et al. pro-thrombotic effects
Phosphorus
Hepatotoxicity
Rat
1998-2012
Phosphorus high dilutions (30x) Bildet 1984, Guillemain protects from toxic hepatitis 1987 Palmerini 1993
Tadpoles Thyroxine
Increases the rate Thyroxine high dilutions (up to of metamorposis 30x) inhibit metamorphosis
Endler 1990-2014, Lingg 2008, Weber 2008, Guedes 2011, Harrer 2013
Rat, Mouse
Gelsemium s.
Toxic and convulsivant
Anxiolytic effect (2c-30c) of Gelsemium s.
Magnani 2010, Venard 2011, Bellavite 2012
Wheat
Arsenic
Cell toxicity
Ars. high dilutions (45x) stimulate vitality
Betti et al. 1997-2014
Cape Town 5 Sept 2018
© P. Bellavite, Università di Verona
PARADOXICAL EFFECTS OF ASPIRIN (1990-2013) and Aguejouf,O.; BelougneMalfatti,E.; Doutremepuich,F.; Belon,P.; Desplat, V;
Dr Christian Doutremepuich
Dr Francisco Eizayaga
Ref: https://www.ncbi.nlm.nih.gov/pubmed/22292117
High dose (500 mg) Low dose (50-100 mg)
«Rebound» effects and High dilutions (9-15-30CH)
Anti-thrombotic (Pro-haemorragic) Cape Town 5 Sept 2018
Pro-thrombotic Adverse «Homeopathic» effect use?
(Anti-haemorragic) © P. Bellavite, Università di Verona
SCIENTIFIC REEVALUATION OF THE HOMEOPATHIC “SIMILE”
IMPORTANT NOTE The inversion of biological effects dependent on the dose of the drug (“hormesis”) has been confirmed in a number of well-designed model systems, but is NOT a general rule for homeopathy. In fact, high homeopathic dilutions (extremely low doses, or «no doses») often act in the same direction of low dilutions (ponderal doses)
Cape Town 5 Sept 2018
© P. Bellavite, Università di Verona
EFFECTS OF HISTAMINE AND ON HUMAN BASOPHILS Chirumbolo , Bellavite et al., Inflammation Research 2009
HISTAMINE
Histamine low dilution (2C, ponderal)
Cape Town 5 Sept 2018
WATER CONTROL
(positive control)
© P. Bellavite, Università di Verona
MODEL OF THE HISTAMINE ACTION ON BASOPHILS AND MAST CELLS (Belon, Mannaioni et al.)
Cape Town 5 Sept 2018
© P. Bellavite, Università di Verona
Action of homeodrugs at receptor level LOW DILUTIONS (e.g. 2CH-5CH)
HIGH DILUTIONS (e.g. 9CH-30CH) CIMETIDINE
H
H
Inhibition of Basophils
Histamine Low dilution PROPRANOLOL
A
Histamine High dilution PROPRANOLOL
Inhibition of Basophils
A
Adrenaline Low dilution
Adrenaline High dilution
Anxiolytic-like effect Gelsemium Gelsemine Low dilution
Gels
Cape Town 5 Sept 2018
STRYCHNINE
Gels
Gelsemium Gelsemine High dilution
© P. Bellavite, Università di Verona
Evidence for homeopathic principles in the basic sciences 1. 2. 3. 4.
Introduction Similia Microdose and «potency» Key points
Note: Tables and figures of this presentation are available at: http://www.paolobellavite.it/news.html Cape Town 5 Sept 2018
© P. Bellavite, Università di Verona
TESTING HOMEOPATHY MAIN HYPOTHESIS IS A SCIENTIFIC ISSUE!
“A medicine whose selection has been accurately homoeopathic must be all the more salutary the more its dose is reduced to the degree of minuteness appropriate for a gentle remedial effect...”
C.F.S. Hahnemann
C.F.S. Hahnemann, 1810 Organon, par. 277 TRUE
FALSE
SCIENTIFIC RESEARCH Cape Town 5 Sept 2018
© P. Bellavite, Università di Verona
The famous and controversial paper of «Water memory» Davenas, E., Benveniste, J., et al. Nature 333: 816-818, 1988.
Jacques Benveniste (1935 – 2004)
Cape Town 5 Sept 2018
© P. Bellavite, Università di Verona
EXAMPLES OF HIGH DILUTION EFFECTS “IN VITRO” System
Agent
Dilution
Human basophils
Apis, Histamine
12C-16C 10-24 10-32
Inhibition of activation markers
Human basophils
Adrenaline
Inhibition of activation markers
Cicken embrio
Bursin
12C-16C 10-24 10-32 15 C (10-27g)
Human neutrophils Wheat germination Rat neurons
Phosphorus
12 D to 30 D
Arsenic Silver nitrate Glutamate
26 D (10-45 )
Neurocytes Bacteria
Cycloheximide Arsenicum
10-27 30C
Neurocytes
Gelsemium s.
2-30 C
Colon cancer cells Macrophages
Ruta grav.
MT-30C
Arnica montana
2-15C
Epitelial cells
Apis mellifera
3-30C
Cape Town 5 Sept 2018
10-18 10-30
Ref.
Effect
Poitevin 1988, Belon 1999-2009 (and Verona Group) Mannaioni et al. 2010
Immunomodulatory and endocrine activity Inhibition of superoxide production Protect from toxicity Enhances growth Protection from glutamate toxicity Increases viability Protects from toxicity Prevalent gene downregulation Decrease viability, apoptotic gene expression Modulates inflammatory genes Modulates hundreds of genes
Bastide, YoubicierSimo 1993-97 Chirumbolo and Bellavite 1993 Betti 1997/2015 Pongratz 1998 Jonas et al., 2001 Marotta 2002 Das et al 2011, De et al 2012 Marzotto 2014, Olioso 2014 Arora and Tandon 2015 Olioso 2016, Marzotto 2016 Bigagli 2016
© P. Bellavite, Università di Verona
Gelsemium sempervirens as a model of laboratory investigation of homeopathy (Verona lab 2008-2018)
Gelsemine
Possible analogy with (SOME) human symptoms Repertorial Materia Medica: Result of search by index in all repertories: [root:WALK] AND [root:AMEL] MIND - ANXIETY - walking - air, in open – amel. 7 MIND - ANXIETY - walking – amel. 8 MIND - WALKING - air; in the open – amel. 20 GENERALS - WALKING - air; in open – amel. 135 GENERALS - WALKING - rapidly – amel. 19 GENERALS - WALKING - slowly – amel. 15 Materia Medica (Boenninghausen, Murphy): MIND: FEELING AS IN DANGER OF FALLING MIND: DREAD/DESIRE OF BEING ALONE MIND: IMPATIENT AND IRRITABLE MIND: NERVOUS DREAD OF APPEARING IN PUBLIC
Cape Town 5 Sept 2018
© P. Bellavite, Università di Verona
C. TIME SPENT IN LIT AREA (anxiolytic-like effect)
EFFECT (% of control placebo)
En field
A. GENERAL MOVEMENT (total distance travelled, movement and possibly sedation)
EFFECT (% of control placebo)
Light Dark
EFFECT (% of control placebo)
Open field
EFFECT (% of control placebo)
Anxiolytic-like effect on mice behaviour (Verona lab 2008-2012) B. TIME SPENT IN CENTRAL AREA (index of exploration attitude)
NO TOXIC EFFECTS
D. LIGHT-DARK transitions (anxiolytic-like effect and movement)
*